The selective cathepsin K inhibitor MIV-711 prevents subchondral and cancellous bone loss in rabbits subjected to anterior cruciate ligament transection

Purpose: Subchondral bone is often affected in osteoarthritis patients. These abnormalities can be manifested as subchondral bone loss, bone sclerosis, bone marrow lesions and osteophyte formation depending on disease stage. We evaluated the effect of anterior cruciate ligament transection (ACLT) on subchondral and cancellous bone in rabbits and whether the selective cathepsin K inhibitor MIV-711 could reverse the ACLT-evoked changes. Methods: New Zealand white rabbits aged 9-10 months old were subjected to ACLT (n = 21) or sham surgery (n = 6) of the right femorotibial joint. One week after surgery, ACLT rabbits were treated with either vehicle (n = 7), 30 μmol/kg (n = 7), or 100 μmol/kg MIV-711 (n = 7), while the sham group received vehicle. Treatments were given orally once daily for 7 weeks until sacrifice. Plasma samples were collected on Days 1, 10, 22 and 45 for determination of MIV-711 concentrations. After sacrifice, subchondral bone parameters were quantified using μCT. Results: Treatment with MIV-711 resulted in a dose-dependent increase in circulating concentrations of MIV-711. Similar pharmacokinetic profiles were seen on each day assessed. ACLT caused thinning of the subchondral bone plate that was dose-dependently reversed by MIV-711. Figure 1 shows subchondral bone plate thickness representative of the group mean values for average plate thickness. ACLT evoked a 14% loss in femur subchondral bone plate thickness compared to the vehicle-treated sham group (sham: 346 ± 6 μm vs. ACLT: 296 ± 16 μm, p < 0.05). The bone loss induced by ACLT was reversed by MIV-711 (30 μmol/kg: 347 ± 10 μm; 100 μmol/kg: 353 ± 8 μm, p < 0.05 vs. ACLT vehicle for both groups). Similar findings were found when assessing femur subchondral bone plate volume (sham: 50.8 ± 2.5 mm3 vs. ACLT: 45.5± 3.1 mm3) with full reversal by MIV-711 (30 μmol/kg: 53.7 ± 0.8 mm3; 100 μmol/kg: 55.6 ± 2.0 mm3, p < 0.05 vs. ACLT vehicle for both groups). ACLT also caused a 15% decrease in tibial subchondral bone plate thickness (sham: 383 ± 19 μm vs. ACLT: 324 ± 14 μm, p < 0.05) which was reversed by MIV-711 (30 μmol/kg: 383 ± 15 μm; 100 μmol/kg: 401 ± 8 μm, p < 0.05 vs. ACLT vehicle for both groups). Tibial subchondral bone volume was decreased by 17% in response to ACLT (sham: 40.3 ± 1.1 mm3 vs. ACLT: 33.4 ± 1.7 mm3) with full reversal by MIV-711 (30 μmol/kg: 39.0 ± 2.0 mm3; 100μmol/kg: 41.2 ± 0.9 mm3, p < 0.05 vs. ACLT vehicle for both groups). In general, the bone loss was most pronounced in lateral sites. Similar trends were seen when evaluating the bone volume fraction (BV/TV) of cancellous bone although with larger variation. Again, the highest degree of ACLT-evoked bone loss was seen in lateral sites. MIV-711 attenuated cancellous bone loss in the lateral femur (BV/TV; sham: 0.383 ± 0.020; ACLT: 0.312 ± 0.018; 30 μmol/kg: 0.342 ± 0.029; 100 μmol/kg: 0.357 ± 0.013) and fully prevented cancellous bone loss in the lateral tibia (BV/TV; sham: 0.497 ± 0.028; ACLT: 0.376 ± 0.031; 30 μmol/kg: 0.460 ± 0.034; 100 μmol/kg: 0.481 ± 0.020, p < 0.05 vs. ACLT vehicle for 100 μmol/kg group). Conclusions: The results demonstrate that ACLT, a preclinical rabbit model of osteoarthritis, causes significant bone loss in the subchondral bone plate and in subchondral cancellous bone in both femur and tibia. The bone loss is reversed by the selective cathepsin K inhibitor MIV-711 at clinically relevant concentrations.